posted on 2024-05-01, 07:20authored byBrandon Cieniewicz, Edson Oliveira, Mike Saxton, Damoun Torabi, Ankit Bhatta, Phanidhar Kukutla, Alexander Arballo, Zhuo Yang, Bi Yu, Maria Fate, Hongxiu Ning, Lawrence Corey, Abhishek Maiti, Daniel Corey
Supplementary materials and methods, tables, and figures
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ARTICLE ABSTRACT
Disruption of lipid bilayer asymmetry is a common feature observed in cancer cells and offers novel routes for therapeutic targeting. We used the natural immune receptor TIM-4 to interrogate for loss of plasma membrane phospholipid polarity in primary acute myelogenous leukemia (AML) samples and evaluated the anti-leukemic activity of TIM-4-L–directed T-cell therapy in preclinical AML models.
We performed FACS analysis on 33 primary AML bone marrow specimens and correlated TIM-4-L expression frequency and intensity with molecular disease characteristics. Using Kasumi-1 and MV-4–11 AML cell lines, we further tested the anti-leukemic effects of TIM-4-L–directed engineered T cells in vitro and in vivo.
We found that 86% of untreated AML blasts displayed upregulation of cell surface TIM-4-L. These observations were agnostic to AML genetic classification, as samples with mutations in TP53, ASXL1, and RUNX1 displayed TIM-4-L upregulation similar to that seen in favorable and intermediate subtypes. TIM-4-L dysregulation was also stably present in AML cell lines. To evaluate the potential of targeting upregulated TIM-4-L with adoptive T-cell therapy, we constructed TIM-4-L–directed engineered T cells, which demonstrated potent anti-leukemic effects, effectively eliminating AML cell lines with a range of endogenous TIM-4-L expression levels both in vitro and in vivo.
These results highlight TIM-4-L as a highly prevalent target on AML across a range of genetic classifications and novel target for T-cell–based therapy in AML. Further investigations into the role of TIM-4-L in AML pathogenesis and its potential as an anti-leukemic target for clinical development are warranted.